ABSTRACT Plasmacytoid dendritic cells (pDCs) represent a distinct innate immune cell type capable of rapid and massive production of type I interferon in response to viruses. pDCs play an important role in both innate and adaptive immune responses to viral infections, whereas aberrant activation of pDCs contributes to autoimmune diseases such as systemic lupus erythematosus. Major questions about the role and molecular basis of pDC function still remain unanswered, largely due to the absence of pDC-specific Cre deleter and fluorescent reporter strains. The overall goal of this project is to develop novel genetic tools for functional analysis of pDCs. In Aim 1, we will use a candidate pDC-specific gene as a driver to express Cre recombinase in pDCs in vivo. We will examine the specificity and efficiency of Cre recombination in the resulting strain and use it in a proof-of-principle gene targeting in vivo. In Aim 2, we will use the same approach to generate a pDC-specific fluorescent reporter strain and use it to explicitly visualize pDC in tissue sections. Collectively, these studies address a major unmet need for model systems to study pDC function, and therefore would facilitate in vivo studies of innate immunity.